2015 St Gallen 化疗及靶向治疗进展.ppt

PI3K/AKT/mTOR 通路在乳腺癌中常过度活化 PI3K/AKT/mTOR 通路在乳腺癌中常过度活化 可能由于1,2 HER2介导的信号上调 PIK3CA突变或扩增 PTEN突变或缺失 PTEN缺失和PIK3CA突变导致 AKT过度活化 PI3K通路信号异常 不可控的细胞代谢增殖和生存 Baselga J. Oncologist. 2011;16(suppl 1):12-19 Agent Target BYL719 P13Kα Ink-1117 P13Kα GDC-0032 P13Kα,δ,? XL-147 Pan-P13k BKM120 Pan-P13k FDC-9041 Pan-P13k PKI-587 Pan-P13k XL-765 P13K/Mtor PF-4691502 P13K/Mtor AZD8055 mTOR(catalytic) INK 128 mTOR(catalytic) MK-2206 AKT1,2,3 GDC-0068 AKT PI3K pathway inhibitors in clinical tials BOLERO-2：PFS PFS HR = 0.38 (95% CI, 0.31-0.48) Log-rank P < .0001 Kaplan-Meier medians EVE 10 mg + EXE: 11.0 mo PBO + EXE: 4.1 mo EVE + EXE PBO + EXE Patients at risk 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 485 239 427 179 359 114 292 76 239 56 211 39 166 31 140 27 108 16 77 13 62 9 48 6 32 4 21 1 18 0 11 0 10 0 5 0 0 0 Censoring times EVE 10 mg + EXE (n/N = 188/485) PBO + EXE (n/N = 132/239) 0 20 40 60 80 100 Probability of Event, % Time, wk Patient Population HR+/HER2- locally advanced MBC Post-menopausal AI Resistant No more than 1 prior chemo line allowed for MBC Measurable lesion or bone lesion mTORi naive Adequate amount of tumor tissue for molecular screening(PI3K pathway activation testing) ENTRY RUN IN Fulvestrant 500mg cycle 1 day 1 RANDOMI ZAT ION stratification Visceral Disease PI3K Pathway status BKM120 100mg daily Fulvestrant day 15 cycle 1 and day 1 every cycle N=421 1:1 N=~842 At least 334 PI3K activated Placebo 100mg daily Fulvestrant day 15 cycle 1 and day 1 every cycle N=421 BKM 120.Pivotal Phase III study in Breast Cancer SCREENING PHASE RUN IN TREA TMENT PHASE RANDOMIZED TREATMENT PHASE SAFETY EFFICACY and SURVIVAL FOLLOW UP PHASE Endpoints (patients group) Co-primary PFS(full) PFS (PI3K activated) Co key secondary OS(full) OS(PI3K activated) Secondary PFS, OS (PI3K non-activated/unknown) ORR, CBR (full, PI3K activated, PI3K non-activated/unknown) Safety (full) BKM 120 and fulvestrant PK EORTC QLQ-C30 (full, PI3K activated) Exploratory Biomarkers Lorele